US3357978A - Process for preparing new benzamides - Google Patents

Process for preparing new benzamides Download PDF

Info

Publication number
US3357978A
US3357978A US348255A US34825564A US3357978A US 3357978 A US3357978 A US 3357978A US 348255 A US348255 A US 348255A US 34825564 A US34825564 A US 34825564A US 3357978 A US3357978 A US 3357978A
Authority
US
United States
Prior art keywords
grams
amino
methoxy
methyl
water
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US348255A
Inventor
Thominet Michel Leon
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Societe dEtudes Scientifiques et Industrielles de lIle de France SA
Original Assignee
Ile De France
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ile De France filed Critical Ile De France
Application granted granted Critical
Publication of US3357978A publication Critical patent/US3357978A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups

Definitions

  • A is selected from the group consisting of lower alkyl and the group a 3HN X is selected from the group consisting of amino, alkylamino, dialkylamino and alkanoylamino;
  • Y is selected from the group consisting of halogen, hydroxy, lower alkoxy, nitro, amino, alkylamino, dialkylamino, alkanoylamino, alkanoyl, mercapto and sulfamoyl;
  • n is a positive whole number less than 4 and greater than 1;
  • R R R and R are selected from the group consisting of lower alkyl and the combinations of R and R and R and R each into heterocyclic rings selected from the group consisting of morpholyl, piperidyl, pyrrolidyl, N-alkyl piperazyl and N-alkylsulfonylpiperazyl; and
  • R is selected from the group consisting of hydrogen and lower alkyl
  • X being an amino, alkylamino, dialkylamino or acylamino radical
  • Y being a halogen, or a hydroxy, alkoxy of low molecular weight, nitro, amino, alkylamino, dialkylamino, acylamino, acyl of low molecular weight, mercapto or sulfamido;
  • n 2 or 3;
  • heterocycle groups can form a heterocycle such as morpholyl, piperidyl, pyrrolidyl, N-alkyl piperazyl, or N-alkylsulfonylpiperazyl.
  • the method of preparing these benzamides employs as starting material p-amino salicyclic acid which is esterified.
  • the amine function of the p-amino salicyclic acid obtained is then acetylated.
  • the phenol function of the acetylated derivative is then alkylated by a suitable alkylating agentalkyl halide, alkyl sulfate, alkyl benzeneor toluene-sulfonate, etc.
  • the substituent is then fixed in 5-position on the ring.
  • the ester function is transformed into an amide function by heating with an asymmetrically disubstituted diamine and the acetylated derivative is hydrolyzed to obtain the corresponding amino derivative.
  • the introduction of the groups Y into the 5-position involve various reactions. Halogens are introduced by direct halogenation in the cold. Chlorine and bromine are the usual halogens introduced.
  • the reaction is carried out in an inert solvent such as acetic acid. Nitration is carried out in a mixed acid, such as nitric and acetic acid. Nitro groups are reduced by catalytic hydrogenation, metal and acid, or similar acid methods to give amino groups.
  • Reductive alkylation such as catalytic reduction in the presence of formaldehyde gives alkylamino groups.
  • 3 amino group is replaced by hydroxyl by means of d-iazotization and hydrolysis and the resulting hydroxyl can be alkylated to alkoxy.
  • STEP B Preparation of methyl p-acetylamino salicylate.
  • a 2-liter flask provided with an agitator, a thermometer and a dropping funnel, there are introduced 361 grams (2.16 mole) of methyl p-amino salicylate and 725 ml. of absolute alcohol.
  • the rather thick paste obtained is heated to 40 C. and a start is then made with pouring therein with agitation, in small portions, 225 grams (2.16 mole) of acetic anhydride.
  • the addition of acetic anhydride is controlled in such a manner that the temperature of the reaction mixture does not exceed 50 C.
  • the pasty mass dissolves gradually and the solution becomes clear toward the end of the addition of the anhydride.
  • the acetylate ester crystallizes in a very thick slurry. It is cooled to 20 C. and 500 ml. of water added, whereupon this reaction mixture is poured into 7 liters of water. It is agitated for 1% hours, centrifuged and washed on a filter with 2 liters of water.
  • STEP D Preparation of methyl 2-meth0xy-4-acetylamin0-5- chlorobenzoate.-Into a 3-liter flask provided with an agitator, a thermometer and a gas inlet tube, there are place 348 grams of methyl-2-methoxy-4-acetylamino benzoate and 1800 ml. of acetic acid. Heating is effected at 30 C. to dissolve the mixture. It is then cooled to about 15 C. and a stream of chlorine introduced while maintaining the temperature between 15 and 20 C. The feeding of the chlorine is stopped when an increase in weight of 112 grams (1.56 moles) is noted. The reaction mixture is poured into 19 liters of water.
  • Step G Preparation of the dihydrochloride of N-(diethylaminoethyl)-2-methoxy-4-amin0-5-chl0r0benzamide.
  • the 260 grams of base obtained in Step F are dissolved in 600 ml. of boiling absolute alcohol. A slight amount of insoluble matter is filtered off.
  • Washing is effected with 200 ml. of alcohol.
  • An alcoholic solution of 73 grams of dry hydrochloric acid dissolved in 250 ml. of absolute alcohol and 20 ml. of water is added. It is set aside for /2 hour and seeded.
  • the crystalline precipitate obtained is centrifuged in the cold, washed carefully with about 200 ml. of alcohol and dried at 40 C. There are obtained 285 grams of the dihydrochloride of N-(diethylaminoethyl)-2-methoXy-4- amino-S-chlorobenzamide. M.P.: 136137 C.
  • Step F Preparation of the dihydroehloride of N-(diethylaminoethyl)-2-methoxy-4-amino-5 brornobenzamide monohydrate.140 grams of the base coming from Step E are dissolved in 420 ml. of alcohol close to the boiling point. The cloudy solution obtained is filtered rapidly. To this solution, cooled to about 50 C. and partially recrystallized, there is added an alcoholic solution of 30 grams of dry hydrochloric acid in 120 ml. of absolute alcohol and ml. of water. There is total redissolving. It is cooled to about 20 C. The crystallization starts to commence. It is set aside overnight in the icebox.
  • STEP D Preparation of methyl-2-ethoxy-4-acetylamino-5-chlorobenzoate.
  • a Z-neck, 6-liter flask with thermometer and gas inlet tube there are placed 198 grams of methyl- 2-et-hoxy-4-acetylaminobenzoate and 2.400 liters of acetic acid. Heating is eflected to about 40 C. to obtain a clear solution. It is cooled to about 15 C. and While maintaining this temperature, a stream of chlorine is passed through until there is an increase in weight of 60 grams. The introduction requires about /2 hour. The reaction mixture is poured into 24 liters of water.
  • Steps A through F when the process of Steps A through F are followed, using p-ethylaminosalicylic acid and p-diethylaminosalicylic acid as the starting material, there are obtained the corresponding 4-ethylamino and diethylamino products.
  • the acylation step is not needed in the latter case.
  • Step P if the addition of soda is omitted, the product being crystallized by addition of water, there is obtained the corresponding 4-acetylamino-5-nitro amide.
  • Step F There is formed at the end of Step F the corresponding N- substituted 2-methoxy-4-amino-S-chlorobenzamide.
  • Example IX N-(diethylaminoethyl)-2-methoxy-4-amino-5-dimethylamino benzamide
  • the reduction of Example VI is carried out by hydrogenation at 40 psi. over Raney nickel in dimethoxyethane containing an excess of 37% aqueous formaldehyde and acetic acid.
  • the product is isolated by filtration, evaporation to dryness, extraction with ether, washing of the extract with aqueous bicarbonate and evaporation of the dried ether solution. It is N-(diethylarninoethyl)-2-methoxy-4-amino-S-dimethylaminobenzamide.
  • Y is selected from the group consisting of halogen, hydroxy, lower alkoxy, nitro, amino, alkylamino, dialkylamino, alkanoylamino, alkanoyl, mercapto and sulfamoyl;
  • n is a positive whole number less than 4 and greater than 1;
  • R R R and R are selected from the group consisting of lower alkyl and together with the nitrogen form morpholino, piperidino, pyrrolidino, N-alkylpiperazino and N-alkylsulfonylpiperazino; and R is selected from the group consisting of hydrogen and lower alkyl, which comprises, in combination, the successive steps of:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

United States Patent 3,357,978 PROCESS FOR PREPARING NEW BENZAMIDES Michel Leon Thominet, Paris, France, assignor to Societe dEtudes Scientifiques et Industrielles de lIle-de-France, Paris, France N Drawing. Filed Feb. 28, 1964, Ser. No. 348,255 Claims priority, application France, Mar. 5, 1963, 926,941 7 Claims. (Cl. 260-2471) This invention relates to a new method of preparing certain benzamides. More specifically, it relates to a new method of preparing benzamides of the formula:
in which:
A is selected from the group consisting of lower alkyl and the group a 3HN X is selected from the group consisting of amino, alkylamino, dialkylamino and alkanoylamino;
Y is selected from the group consisting of halogen, hydroxy, lower alkoxy, nitro, amino, alkylamino, dialkylamino, alkanoylamino, alkanoyl, mercapto and sulfamoyl;
n is a positive whole number less than 4 and greater than 1;
R R R and R are selected from the group consisting of lower alkyl and the combinations of R and R and R and R each into heterocyclic rings selected from the group consisting of morpholyl, piperidyl, pyrrolidyl, N-alkyl piperazyl and N-alkylsulfonylpiperazyl; and
R is selected from the group consisting of hydrogen and lower alkyl; 1
which comprises the combination, in this specific order, of the steps of esterifying p-aminosalicyclic acid, acylating the amino group, alkylating the phenolic hydroxyl, introducing the group Y into the ring, condensing the product with the amine and deacylating the p-arnino group.
In French Patents 1,159,180 of Apr. 28, 1954, 1,311,114 of Apr. 5, 1960 and 1,313,758 of July 25, 1962, the preparation of substituted N-tertiary aminoalkyl benzamides has already been described. For this purpose a substituted acid chloride is reacted with an asymmetric disubstituted diamine in a reaction medium such that the benzamide hydrochloride formed can be recovered in pure state by filtration or centrifuging.
It has been found during the course of further studiesand this constitutes the object of the present invention 3,357,978 Patented Dec. 12, 1967 "ice that one could prepare in an original manner subsituted benzamides of the formula:
X being an amino, alkylamino, dialkylamino or acylamino radical;
Y being a halogen, or a hydroxy, alkoxy of low molecular weight, nitro, amino, alkylamino, dialkylamino, acylamino, acyl of low molecular weight, mercapto or sulfamido;
n being equal to 2 or 3;
one of the CH groups of A or of the carboxamide function can be branched in the form 1'1, with for instance R =CH R R R R are identical or different alkyl radicals of low molecular weight;
The
groups can form a heterocycle such as morpholyl, piperidyl, pyrrolidyl, N-alkyl piperazyl, or N-alkylsulfonylpiperazyl.
In accordance with this invention, the method of preparing these benzamides employs as starting material p-amino salicyclic acid which is esterified. The amine function of the p-amino salicyclic acid obtained is then acetylated. The phenol function of the acetylated derivative is then alkylated by a suitable alkylating agentalkyl halide, alkyl sulfate, alkyl benzeneor toluene-sulfonate, etc. The substituent is then fixed in 5-position on the ring. The ester function is transformed into an amide function by heating with an asymmetrically disubstituted diamine and the acetylated derivative is hydrolyzed to obtain the corresponding amino derivative.
The introduction of the groups Y into the 5-position involve various reactions. Halogens are introduced by direct halogenation in the cold. Chlorine and bromine are the usual halogens introduced. The reaction is carried out in an inert solvent such as acetic acid. Nitration is carried out in a mixed acid, such as nitric and acetic acid. Nitro groups are reduced by catalytic hydrogenation, metal and acid, or similar acid methods to give amino groups. Reductive alkylation, such as catalytic reduction in the presence of formaldehyde gives alkylamino groups. The
3 amino group is replaced by hydroxyl by means of d-iazotization and hydrolysis and the resulting hydroxyl can be alkylated to alkoxy.
These various stages of the synthesis can be clarified, by way of example, in the case of a halogen bound in position on the ring, by the table appended at the end of the present patent.
The preparation of the following compounds is given by way of illustration and without in any way limiting the invention.
EXAMPLE I Dihydrochloride of N-(diethylaminoethyl) -2-methoxy- 4-amino-S-chlorobenzamide 'STEP A Preparation of methyl p-amino salicylate.-In a 6-liter flask provided with a mechanical agitator and a reflux condenser, there are introduced 1875 grams of absolute methanol and then, in small portions, while cooling, 970 grams of sulfuric acid of 93% purity and finally 383 grams (2.5 mole) of p-amino salicylic acid (PAS). The resultant suspension is heated under reflux with agitation for 5 to 6 hours. The dissolving takes place rather rapidly. It is cooled to about 30 C. and the mixture then poured with agitation into a solution of 12.5 liters of water containing 975 grams of dry sodium carbonate. The methyl p-amino salicylate formed precipitates out in solid state. It is centrifuged, and washed with water until disappearance of the sulfate ions. The product is then dried at 60 C.; there are obtained 361 grams of crystals melting at 119 C. (yield 86%).
STEP B Preparation of methyl p-acetylamino salicylate.Into a 2-liter flask provided with an agitator, a thermometer and a dropping funnel, there are introduced 361 grams (2.16 mole) of methyl p-amino salicylate and 725 ml. of absolute alcohol. The rather thick paste obtained is heated to 40 C. and a start is then made with pouring therein with agitation, in small portions, 225 grams (2.16 mole) of acetic anhydride. The addition of acetic anhydride is controlled in such a manner that the temperature of the reaction mixture does not exceed 50 C. The pasty mass dissolves gradually and the solution becomes clear toward the end of the addition of the anhydride. About onequarter of an hour after the end of the anhydride addition, the acetylate ester crystallizes in a very thick slurry. It is cooled to 20 C. and 500 ml. of water added, whereupon this reaction mixture is poured into 7 liters of water. It is agitated for 1% hours, centrifuged and washed on a filter with 2 liters of water.
The precipitate is dried at 55 to 60 C. There are obtained 427 grams of methyl p-acetylarnino salicylate (yield 94%). M.P.: 152 to 153 C. I
STEP C Preparation of methyl-2-methoxy-4-acetylamino benzoate-Into a 5-liter flask provided with an agitator and a reflux condenser, there are placed 427 grams of methyl p-acetylamino saliclylate and 1500' ml. of acetone. Heating is effected until dissolved (about 48 C.). 276grams (2 mole) of potassium carbonate and then 277 grams (2 mole+%) of methyl sulfate are then rapidly added. Heating is continued until the mixture boils. There is very rapidly noted a great thickening of the reaction mixture which is very difficult to agitate. About minutes after the addition of the methyl sulfate, the reaction mixture becomes fluid. Heating is continued under reflux for 15 hours; about 1.200 liters of acetone are then distilled 011?, and the residue is cooled to about 50 C. and diluted with 2.500 liters of water. The methyl Z-methoxy-4-aeety1amino benzoate formed precipitates. It is set aside overnight, centrifuged and Washed until neutral. The precipitate is then dried at about 55-60 C. There are obtained 348 grams of product (yield 78.5%). M. P.: 127 C.
STEP D Preparation of methyl 2-meth0xy-4-acetylamin0-5- chlorobenzoate.-Into a 3-liter flask provided with an agitator, a thermometer and a gas inlet tube, there are place 348 grams of methyl-2-methoxy-4-acetylamino benzoate and 1800 ml. of acetic acid. Heating is effected at 30 C. to dissolve the mixture. It is then cooled to about 15 C. and a stream of chlorine introduced while maintaining the temperature between 15 and 20 C. The feeding of the chlorine is stopped when an increase in weight of 112 grams (1.56 moles) is noted. The reaction mixture is poured into 19 liters of water. The precipitate is set aside for one hour, centrifuged and washed with water until disappearance of the chlorine ions. It is then dried at 60 C. There are obtained 345 grams of methyl 2-methoxy- 4-acetylamino-S-chlorobenzoate (yield: 86% M.P. 153 C.
STEP E Preparation of N (diethylaminoethyl)-2-methoxy-4- acetylamina-S-chlorobenzamide.Into a 5-liter flask provided with an agitator and a Vigreux distillation column of a height of about 30 cm., there are introduced 345 grams of methyl-2-methoxy-4-acetylarnino-S-chlorobenzoate, 670 ml. of xylene and 156 grams of N,N-diethylethylene diamine. The mixture partially dissolves. 67 grams of aluminum isopropylate are then added. It is heated gently at the boiling point so that the temperature of the solution at the top of the column is maintained between 65 and C. maximum (xylenemethanol azeotrope 6365 C.). In 2 /2 hours, there are collected ml. of distillate corresponding to 50 ml. of methanol. The fraction passing over at about C. (xylene) is then distilled again for 1% hours and then allowed to cool. Crystallization takes place. The crystals are taken up with 1600 ml. of water and about 400 ml. of concentrated hydrochloric acid; there is practically complete dissolving of the mixture which is filtered. The xylene layer is decanted and the aqueous solution is reprecipitated by a 30% excess of soda (600 ml.). The base is precipitated, centrifuged in the cold and washed with water. The product is kept as is to be subjected immediately to hydrolysis.
STEP F Preparation of N (diethylaminoethyl)-2-meth0xy-4- amino-5-chl0r0benzamide.-The crude product obtained in the preceding step is treated with 1340 m1. of concentrated hydrochloric acid and 2200 ml. of water. The resultant mixture is boiled for 1% hours under reflux. The reaction product is then boiled for 10 minutes with 2 or 3 grams of animal charcoal. It is cooled and filtered. The filtered solution is precipitated with soda until alkalined by phthalein. The crystalline product obtained is centrifuged and washed with water until disappearance of the a chlorine ions. In this way there are obtained 260 grams of N (diethylaminoethyl) 2-methoxy-4-amino-5-chlorobenzamide. M.P. 144 C. (Total yield of Steps E and F: 65%.)
STEP G Preparation of the dihydrochloride of N-(diethylaminoethyl)-2-methoxy-4-amin0-5-chl0r0benzamide.The 260 grams of base obtained in Step F are dissolved in 600 ml. of boiling absolute alcohol. A slight amount of insoluble matter is filtered off.
Washing is effected with 200 ml. of alcohol. An alcoholic solution of 73 grams of dry hydrochloric acid dissolved in 250 ml. of absolute alcohol and 20 ml. of water is added. It is set aside for /2 hour and seeded. The crystalline precipitate obtained is centrifuged in the cold, washed carefully with about 200 ml. of alcohol and dried at 40 C. There are obtained 285 grams of the dihydrochloride of N-(diethylaminoethyl)-2-methoXy-4- amino-S-chlorobenzamide. M.P.: 136137 C.
Dihydrochloride of N-(diethylaminoethyl)-2-methoxy-4- amino-S-bromobenzamide Steps A, B and C of this preparation are the same as those described in Example I.
STEP D Preparation of methyl-Z-melhoxy 4 ac'etylamino 5- brombenz0ate.-In a 2-liter flask provided with agitator, a thermometer and a dropping funnel, there are placed 117 grams (0.524 mole) of methyl-2-methoxy-4- acetylaminobenzoate and 585 ml. of acetic acid. Heating is effected at 40 C. until complete dissolving is obtained, followed then by cooling to 15 C. Into the resultant cloudy solution, there are introduced, drop by drop, in the course of one hour, while maintaining the temperature between 15 and 20 C., 87 grams of bromine (0.524 mole+4% excess). There is a slight liberation of hydrobromic acid and toward the middle of the reaction, the bromine derivative formed crystallizes. After the introduction has been completed, the reaction mixture is poured into 5.850 liters of water. The precipitate is centrifuged, washed with water until the disappearance of the bromine ions and dried in anoven at 40 C. There are obtained 152 grams (yield: 96%) of methyl-2-methoxy-4-acetylamino-5-bromobenzoate. M.P.: 174 C.
STEP E Preparation of N-(diethylaminoethyl)-2 methoxy 4- amino-S-br0mobenzamide.-1nto a 2-liter flask provided with a reflux condenser, there are introduced 152 grams of methyl-Z-methoxy-4-acetylamino-5 bromobenzoate, 460 ml. of ethylene glycol and 174 grams (3 times the theoretical quantity) of N,N diethylethylenediamine. Heating is effected on an oil bath at 120 C. under a nitrogen atmosphere for 2 hours.
The dissolving is complete upon the start of the heating. At the end of 2 hours, without cooling, the reaction mixture is transferred into a 5-liter flask provided with a reflux condenser and there are added 460 ml. of 2.5 N soda which has been previously heated to 95 to 100 C. Heating is effected under reflux for 30 minutes in a nitrogen atmosphere. Two layers are formed, the oily amine layer settles in the bottom of the flask. Upon cooling and agitation, this layer solidifies. The mixture is diluted with 460 ml. of water and agitated further for a quarter of an hour. The precipitate formed is centrifuged, washed with water and dried in the oven at 50 C. There are obtained 140 grams of N-(diethylaminoethyl)-2-methoxy-4-amino 5 brornobenzamide (yield: 81%); M.P.: 149 C.
STEP F Preparation of the dihydroehloride of N-(diethylaminoethyl)-2-methoxy-4-amino-5 brornobenzamide monohydrate.140 grams of the base coming from Step E are dissolved in 420 ml. of alcohol close to the boiling point. The cloudy solution obtained is filtered rapidly. To this solution, cooled to about 50 C. and partially recrystallized, there is added an alcoholic solution of 30 grams of dry hydrochloric acid in 120 ml. of absolute alcohol and ml. of water. There is total redissolving. It is cooled to about 20 C. The crystallization starts to commence. It is set aside overnight in the icebox. The next day the precipitate is filtered, washed on the filter with 70 ml. of absolute alcohol and dried at 40 C. There are obtained 132 grams of dihydrochloride crystallizing with one mole of water (yield: 74%). M.P.: 134-l36 C.
EXAMPLE III Hydrochloride of N-(dieth ylaminoethyl) 2 ethoxy 4- amino-S-chlorobenzamide Steps A and B are identical to those described in Example I of the present patent.
STEP C Preparation of methyl-Z-ethoxy 4 acetylaminobenzoate.In a Z-neck 3-liter flask with agitator, reflux condenser and thermometer, there are placed 180 grams (0.86 mole) of methyl-4-acetylamino salicylate and 645 ml.v of acetone. It is heated to 40 C. to obtain a clear solution. There are then rapidly added 119 grams (0.86 mole) of anhydrous potassium carbonate and 146 grams (0.86 mole+10% excess) of ethyl sulfate. Heating under reflux is efiected for 19hours. Thereupon about 440 ml. of acetone are distilled. The product crystallizes. 2.500 liters of water are added to the cooled solution. The product is centrifuged, and washed on the filter with Water. There are obtained 198 grams (97%) of methyl- 2-ethoxy-4-acetylaminobenzoate. M.P.: 145 C.
STEP D Preparation of methyl-2-ethoxy-4-acetylamino-5-chlorobenzoate.Into a Z-neck, 6-liter flask with thermometer and gas inlet tube, there are placed 198 grams of methyl- 2-et-hoxy-4-acetylaminobenzoate and 2.400 liters of acetic acid. Heating is eflected to about 40 C. to obtain a clear solution. It is cooled to about 15 C. and While maintaining this temperature, a stream of chlorine is passed through until there is an increase in weight of 60 grams. The introduction requires about /2 hour. The reaction mixture is poured into 24 liters of water. The resultant precipitate is centrifuged, washed with water until the disappearance of the chlorine ions, and dried in an oven at 40 C. There are obtained 191 grams (yield: 83%) of methyl-2-ethoxy-4-acetylamino-S-chlorobenzoate. MP: 142 C.
STEP E Preparation of N (diethylaminoethyl) 2 ethoxy -4- amino-5-chlorobenzamide.lnto a 3-liter flask with reflux condenser, there are introduced 191 grams of methyl- 2-ethoxy-4-acetylamino-S-chlorobenzoate and 640 ml. of ethylene glycol and 243 grams (3 times the theoretical quantity) of N,N-diethylethylenediamine. Heating is effected at 120 C. on an oil bath for 2% hours. The reaction mixture is poured into a 5-liter flask and 640 ml. of 2.5 N soda which has been previously heated to --100 C. are added. A very abundant precipitate is then obtained, and the heating under reflux is continued for /2 hour. The mixture is cooled and diluted with 640 ml. of water. The product is centrifuged, washed with water until neutral and dried in an oven at 40 C. There are obtained 191 grams (yield: 86.5%) of N-(diethylaminoethyl) 2 ethoxy 4 amino-S-chlorobenzamide, M.P.: 151-152 C.
STEP F Preparation of N (diethylaminoethyl) -2 ethoxy 4- amino-S-chlor0benzamide.By operating as in Step G of Example I, the corresponding hydrochloride is obtained from the base obtained in the previous step. M.P.: 175180 C. (with decomposition).
EXAMPLE IV N- (diethylaminopropyl) -2melhoxy-4-amin0-5-chZorobenzamide Steps A, B, C, and D of this preparation are similar to those described in Example I of the present patent.
STEP E Preparation of N-(diethylamz'nopropyl)-2-methoxy-4- amino-5-chlorobenzamide.In a two-liter flask, there is heated for three hours on an oil bath at C. a mixture of 78 grams (0.3 mole) of methyl-2-methoxy-4-acetylamino-S-chlorobenzoate, 78 grams (0.6 mole) of diethylaminopropylamine and 235 ml. of ethylene glycol. To the resultant hot solution, there are added 240 ml. of a boiling 2.5 N soda solution. Heating is effected under reflux for 30 minutes. Dilution is effected with 2 liters of water. The benzamide formed crystallizes. It is centrifuged and washed abundantly with water. There are obtained 70 grams of N-(diethylaminopropyl)-2-methoxy-4-amino- S-chlorobenzamide (yield: 74%). M.P.: 79-80 C. This base gives a monohydrochloride. M.P.: 188-189 C.
EXAMPLE V Hydrochloride of N-(dz'ethylaminoethyl)-2-meth0xy- 4-amin0-5-nitr0benzamide Steps A, B, and C of this preparation are the same as those described in Example I.
STEP D Preparation of methyl-2-methoxy-4-acetylamin0-5-nitr0- benzoate.-In a 2-liter flask provided with agitator, thermometer and a dropping funnel, there are dissolved 223 grams (1 mole) of methyl-2-methoxy-4-acety1aminobenzoate and 337 grams of acetic anhydride. A slight heating is effected to facilitate this dissolving, the mixture is cooled to C. and 106 grams of fuming nitric acid (D=1.49) dissolved in 75 ml. of acetic acid are added, drop by drop, with agitation. The temperature is maintained at about C. The nitro derivative formed crystallizes during the course of the reaction.
The reaction mixture is cooled and poured into 5 liters of water. It is centrifuged, washed with Water and dried. There are obtained 183 grams (yield: 68%) of methyl-2- methoxy-4-acetylamino-5-nitrobenzoate.
STEP E N-(diethylaminoethyl)-2-methoxy-4 amino 5 nitrobenzamide.lnto a 3 liter flask, there are introduced 183 grams of methyl-2-methoxy-4 acetylamino-S nitrobenzoate, 540 grams of ethylene glycol and 237 grams of N,N-diethylethylenediarnine. The mixture is heated at C. for 100 hours. The flask is then placed on an oil bath at 100 C. and 520 ml. of 2.5 N soda previously heated to about 95 C. are added. The heating is continued for an hour and a half at 100 C., which results in a liquefaction of the mixture. It is taken up in 600 ml. of water. It is cooled, and the compound formed crystallizes. The latter is centrifuged, washed with water until the wash waters are no longer basic, and then dried at C. There are obtained 95 grams of N-(diethylaminoethyl)-2-methoxy 4 amino 5 nitrobenzamide (yield: 45%). M.P.: 2089 C.
STEP F Preparation of hydrochloride of N-(diethylaminoelhyl) -2-mezh0xy4-amin0-5-nitro benzamide.-Following the same technique as that described in Step G of Example I, one obtains from the base obtained in Step E the corresponding monohydrochloride. M.P.: 178179 C.
Similarly, when the process of Steps A through F are followed, using p-ethylaminosalicylic acid and p-diethylaminosalicylic acid as the starting material, there are obtained the corresponding 4-ethylamino and diethylamino products. The acylation step is not needed in the latter case.
In Step P, if the addition of soda is omitted, the product being crystallized by addition of water, there is obtained the corresponding 4-acetylamino-5-nitro amide.
EXAMPLE VI Dihydroclzloride of N-(diethylaminoethyl)-2-meth0xy- 4,5-diamin0 benzamia'e ethylaminoethyl) 2 methoxy 4,5-diaminobenzamide, which gives a dihydrochloride. M.P.: 190-191 C. (with decomposition) Similarly, catalytic reduction of the N-(diethylaminoethyl)-2-methoxy-4-acetamido-S-nitrobenzamide gives N- (diethylaminoethyl)-4-acetamido-5-aminobenzamide.
8 EXAMPLE VII There is formed at the end of Step F the corresponding N- substituted 2-methoxy-4-amino-S-chlorobenzamide.
EXAMPLE VIII When, in Step C of Example I, there is used an equivalent quantity of diethyl sulfate in place of methyl sulfate, the product obtained in Step F is N-diethylaminoethyl-Z- ethoxy-4-amino-5-chlorobenzarnide.
Similarly, when diethylaminoethylbromide is used in place of methyl sulfate, the corresponding Z-diethylaminoethoxy compound is obtained.
EXAMPLE IX N-(diethylaminoethyl)-2-methoxy-4-amino-5-dimethylamino benzamide The reduction of Example VI is carried out by hydrogenation at 40 psi. over Raney nickel in dimethoxyethane containing an excess of 37% aqueous formaldehyde and acetic acid. The product is isolated by filtration, evaporation to dryness, extraction with ether, washing of the extract with aqueous bicarbonate and evaporation of the dried ether solution. It is N-(diethylarninoethyl)-2-methoxy-4-amino-S-dimethylaminobenzamide.
COOH
COOR
(300R O-orr (DOOR -0H NHCOR COOR NHCOR' O O O R NHCOR' COOR NHCOR' (DOOR NI'ICOR S 0 4( a for example R1 ClONH(OHz)nN Hal- Eal- I NHCOR Nrroo R R1 CONH(CH2)nN A O A hydrolysis Hal Hal- NHCOR NH:
I claim: 1. A method of preparing a compound of the formula:
$3 R1 CIJONH(CH) FN in which A is selected from the group consisting of lower alkyl and the group X is selected from the group consisting of amino, alkylamino, dialkylamino and alkanoylamino;
Y is selected from the group consisting of halogen, hydroxy, lower alkoxy, nitro, amino, alkylamino, dialkylamino, alkanoylamino, alkanoyl, mercapto and sulfamoyl;
n is a positive whole number less than 4 and greater than 1;
R R R and R are selected from the group consisting of lower alkyl and together with the nitrogen form morpholino, piperidino, pyrrolidino, N-alkylpiperazino and N-alkylsulfonylpiperazino; and R is selected from the group consisting of hydrogen and lower alkyl, which comprises, in combination, the successive steps of:
(a) esterifying p-aminosalicylic acid; (b) acylation of the amino group of the resulting p-aminosalicylate with a lower alkanoic acid; (c) alkylating the o-hydroxy group of the product of step (b) with a group A, as defined above; (d) introducing the group Y into the product of p (e) heating the product of step (d) with an amine of the structure:
References Cited FOREIGN PATENTS 1,313,758 11/1962 France.
NICHOLAS S. RIZZO, Primary Examiner. I. TOVAR, Assistant Examiner.
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,357,978 December 12, 1967 Michel Leon Thominet It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below Column 2, lines 37 to 40, the second formula should appear as shown below instead of as in the patent:
Signed and sealed this 11th day of February 1969.
(SEAL) Attest:
EDWARD J. BRENNER Commissioner of Patents Edward M. Fletcher, Jr.
Attesting Officer

Claims (1)

1. A METHOD OF PREPARING A COMPOUND OF THE FORMULA:
US348255A 1963-03-05 1964-02-28 Process for preparing new benzamides Expired - Lifetime US3357978A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR926941A FR1407055A (en) 1963-03-05 1963-03-05 New process for the preparation of substituted benzamides
DES0090796 1964-04-27
BE648164A BE648164A (en) 1963-03-05 1964-05-20

Publications (1)

Publication Number Publication Date
US3357978A true US3357978A (en) 1967-12-12

Family

ID=27158988

Family Applications (1)

Application Number Title Priority Date Filing Date
US348255A Expired - Lifetime US3357978A (en) 1963-03-05 1964-02-28 Process for preparing new benzamides

Country Status (3)

Country Link
US (1) US3357978A (en)
BE (1) BE648164A (en)
FR (1) FR1407055A (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3507875A (en) * 1965-01-19 1970-04-21 Sandoz Ag Basically substituted benzoic acid amides
DE2102848A1 (en) * 1970-01-21 1971-10-21 Delmar Chemicals Ltd., LaSaIIe, Quebec (Kanada) Processes and intermediates for the manufacture of benzamides
DE2166456A1 (en) * 1971-01-21 1974-04-11 Delmar Chem 4-amino-5-halo-2-substd benzamides prepn
JPS5032144A (en) * 1973-07-12 1975-03-28
JPS5076039A (en) * 1973-09-27 1975-06-21
US3975443A (en) * 1972-06-06 1976-08-17 Allen & Hanburys Limited 1-(3,4-dichlorobenzamidomethyl)-cyclohexyldimethylamine
US4156779A (en) * 1977-04-26 1979-05-29 Schering Aktiengesellschaft Piperazine and piperidine enamines having an hydroxy group
US4213983A (en) * 1976-11-05 1980-07-22 Beecham Group Limited Treating gastro-intestinal disorders and emesis with n-(heterocyclic substituted) benzamides
US4301159A (en) * 1980-06-20 1981-11-17 Shionogi & Co., Ltd. N-(Diethylaminoethyl)-2-alkoxy-benzamide derivatives
US4476804A (en) * 1982-01-29 1984-10-16 Glatt Maschinen-Und Apparatebau Ag Process of coating of particles, particularly particles of medicinal drugs, and apparatus for implementation of the process
US4808624A (en) * 1984-06-28 1989-02-28 Bristol-Myers Company Pharmacologically active substituted benzamides
US5011992A (en) * 1984-06-28 1991-04-30 Bristol-Myers Squibb Company Pharmacologically active substituted benzamides
US5081258A (en) * 1988-05-19 1992-01-14 E. I. Du Pont De Nemours And Company Bisbenzotriazoleureas as UV stabilizers for polymers
CN110143892A (en) * 2019-06-21 2019-08-20 江苏豪森药业集团有限公司 The preparation method of Mosapride intermediate
CN113698321A (en) * 2021-09-30 2021-11-26 内蒙古康普药业有限公司 New metoclopramide diamine impurity and application

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3700719A (en) * 1968-12-02 1972-10-24 Yamanouchi Pharma Co Ltd Processes for the preparation of n-(diethylaminoethyl)-4-amino-5-chloro-2-methoxybenzamide
JPS4969627A (en) * 1972-10-31 1974-07-05
JPS4970943A (en) * 1972-11-09 1974-07-09
GB1574418A (en) * 1976-11-16 1980-09-03 Anphar Sa Piperidine derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1313758A (en) * 1961-07-25 1963-01-04 Ile De France New substituted benzamides and their preparation process

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1313758A (en) * 1961-07-25 1963-01-04 Ile De France New substituted benzamides and their preparation process

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3507875A (en) * 1965-01-19 1970-04-21 Sandoz Ag Basically substituted benzoic acid amides
DE2102848A1 (en) * 1970-01-21 1971-10-21 Delmar Chemicals Ltd., LaSaIIe, Quebec (Kanada) Processes and intermediates for the manufacture of benzamides
DE2166456A1 (en) * 1971-01-21 1974-04-11 Delmar Chem 4-amino-5-halo-2-substd benzamides prepn
US3975443A (en) * 1972-06-06 1976-08-17 Allen & Hanburys Limited 1-(3,4-dichlorobenzamidomethyl)-cyclohexyldimethylamine
JPS5032144A (en) * 1973-07-12 1975-03-28
JPS5076039A (en) * 1973-09-27 1975-06-21
US4213983A (en) * 1976-11-05 1980-07-22 Beecham Group Limited Treating gastro-intestinal disorders and emesis with n-(heterocyclic substituted) benzamides
US4156779A (en) * 1977-04-26 1979-05-29 Schering Aktiengesellschaft Piperazine and piperidine enamines having an hydroxy group
US4301159A (en) * 1980-06-20 1981-11-17 Shionogi & Co., Ltd. N-(Diethylaminoethyl)-2-alkoxy-benzamide derivatives
US4476804A (en) * 1982-01-29 1984-10-16 Glatt Maschinen-Und Apparatebau Ag Process of coating of particles, particularly particles of medicinal drugs, and apparatus for implementation of the process
US4808624A (en) * 1984-06-28 1989-02-28 Bristol-Myers Company Pharmacologically active substituted benzamides
US5011992A (en) * 1984-06-28 1991-04-30 Bristol-Myers Squibb Company Pharmacologically active substituted benzamides
AT394363B (en) * 1984-06-28 1992-03-25 Bristol Myers Squibb Co METHOD FOR PRODUCING NEW SUBSTITUTED BENZAMIDES
US5081258A (en) * 1988-05-19 1992-01-14 E. I. Du Pont De Nemours And Company Bisbenzotriazoleureas as UV stabilizers for polymers
CN110143892A (en) * 2019-06-21 2019-08-20 江苏豪森药业集团有限公司 The preparation method of Mosapride intermediate
CN110143892B (en) * 2019-06-21 2022-08-12 江苏豪森药业集团有限公司 Preparation method of mosapride intermediate
CN113698321A (en) * 2021-09-30 2021-11-26 内蒙古康普药业有限公司 New metoclopramide diamine impurity and application

Also Published As

Publication number Publication date
FR1407055A (en) 1965-07-30
BE648164A (en) 1964-11-20

Similar Documents

Publication Publication Date Title
US3357978A (en) Process for preparing new benzamides
US3635982A (en) Amino-substituted-quinoxalinyloxazolidines and -oxazines
US2441498A (en) Alkyl glycinanilides
SU1238730A3 (en) Method of producing derivatives of 1,4-dihydropyridine or acid-additive salts thereof
SU504480A3 (en) Method for producing amides of (1 (-phenylalkyl) -piperidyl-4 -) - (-pyridyl) -carboxylic acid or their salts
PL71391B1 (en) 3-alkoxy-thia naphthene-2-carboxamides [us3745175a]
US3923813A (en) Derivatives of 2-aminoindanes
US2502451A (en) Amino-alkyl esters of diphenylamine 2-monocarboxylic acids
GB2067215A (en) Xanthene compounds
US3200151A (en) Arylaminoalkyl guanidines
US3413339A (en) Amine compounds and methods for their production
US3112310A (en) 10-alkylaminoalkylphenothiazine-2-carboxamides
PL75064B1 (en)
PL94114B1 (en)
US2855398A (en) Amidines of the indole series
CA1055502A (en) Process for the preparation of 2,5-disubstituted benzamides
SU449487A3 (en) The method of obtaining 4-amino-6,7,8-trialkoxy-quinazolines
SU528035A3 (en) The method of obtaining derivatives of isoquinoline or their salts
US3954763A (en) N-Metatrifluoromethylthiophenyl-piperazine
US2528940A (en) Pyrrolidylethyl indole compounds
US2783245A (en) Process of phthaloylation amino acids
US2694069A (en) Basic esters of hydroxy-and alkoxy-substituted phenyloxoalkenoic acids and their salts
US2370015A (en) Derivatives of tertiary amino aliphatic acids
US2414050A (en) Condensation derivatives of organic quaternary ammonium compounds
US2992221A (en) Polymethylene-oxoquinazolines and their production